This document presents a new RP-HPLC method for determining logPoct values, a measure of lipophilicity important for drug discovery. The key advantages of the method are that it is rapid (determinations in 20 minutes on average), uses small amounts of compound (1 mL of a 30-50 μg/mL solution), has a wide dynamic range of 6 log units, and shows good accuracy and reproducibility when tested on 36 drug molecules. A comparison to experimentally determined logPoct values indicates the new RP-HPLC method performs comparably to traditional shake-flask methods.
ElogDoct: A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic ...Brian Bissett
I received a nice acknowledgement in this paper.
ElogDoct: A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic and Neutral Compounds
Franco Lombardo, Marina Y. Shalaeva, Karl A. Tupper, and Feng Gao
Molecular Properties Group and Mathematical and Statistical Sciences Group, Pfizer Global Research and Development
A poor solubility in water limits in a drastic way the effi cacy of a drug, because the absorption phenomenon requires the drugs be in dissolution. The therapeutic activity of a drug is depending of its acid-base dissociation constant (pKa) and solubility, the knowledge of pKa values being thus of great worth. The solubility method can be very useful in spite of their limitations if an appropriate method is available to carry out the solubility measurements of scarce solubility compounds. Some examples taken from the bibliography whose behaviour is well adapted to conventional acid-base dissociation equilibria without further complications are selected for study: Calcein blue, butaperazine, sulfadiazine, tyrosine, 8-hydroxiquinoleine and nifl umic acid. The pKa values have been recalculated applying the single least squares method and the classic monoprotic acid bilogarithmic model. A slope-intercept procedure is also applied to get the evaluation of acidity constants of overlapping equilibria (pKa2 and pKa3 of tyrosine). Results obtained in all cases are compared with literature data.
ElogDoct: A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic ...Brian Bissett
I received a nice acknowledgement in this paper.
ElogDoct: A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic and Neutral Compounds
Franco Lombardo, Marina Y. Shalaeva, Karl A. Tupper, and Feng Gao
Molecular Properties Group and Mathematical and Statistical Sciences Group, Pfizer Global Research and Development
A poor solubility in water limits in a drastic way the effi cacy of a drug, because the absorption phenomenon requires the drugs be in dissolution. The therapeutic activity of a drug is depending of its acid-base dissociation constant (pKa) and solubility, the knowledge of pKa values being thus of great worth. The solubility method can be very useful in spite of their limitations if an appropriate method is available to carry out the solubility measurements of scarce solubility compounds. Some examples taken from the bibliography whose behaviour is well adapted to conventional acid-base dissociation equilibria without further complications are selected for study: Calcein blue, butaperazine, sulfadiazine, tyrosine, 8-hydroxiquinoleine and nifl umic acid. The pKa values have been recalculated applying the single least squares method and the classic monoprotic acid bilogarithmic model. A slope-intercept procedure is also applied to get the evaluation of acidity constants of overlapping equilibria (pKa2 and pKa3 of tyrosine). Results obtained in all cases are compared with literature data.
Reactor Metabolizer virtual reactions for discovery: US UGM 2008ChemAxon
ChemAxon developed a unique virtual reaction technology that could be applied in various areas of molecule transformations. Reactor is a virtual combichem application providing synthetically feasible products using generic reactions. No reagent selection is required, and built in rules can provide chemo- regio- and stereospecificity during the library enumeration progress. A new application using the same reaction engine is introduced for the first time for the prediction of metabolic stability and xenobiotic metabolites. For latest developments see: http://www.chemaxon.com/product/reactor.html
Kinetics of Ruthenium(III) Catalyzed and Uncatalyzed Oxidation of Monoethanol...Ratnakaram Venkata Nadh
Kinetics of uncatalyzed and ruthenium(III) catalyzed oxidation of monoethanolamine by N-bromosuccinimide
(NBS) has been studied in an aqueous acetic acid medium in the presence of sodium acetate
and perchloric acid, respectively. In the uncatalyzed oxidation the kinetic orders are: the first order in NBS,
a fractional order in the substrate. The rate of the reaction increased with an increase in the sodium acetate
concentration and decreased with an increase in the perchloric acid concentration. This indicates that free
amine molecules are the reactive species. Addition of halide ions results in a decrease in the kinetic rate,
which is noteworthy. Both in absence and presence of a catalyst, a decrease in the dielectric constant of the
medium decreases the kinetic rate pointing out that these are dipole—dipole reactions. A relatively higher
oxidation state of ruthenium i.e., Ru(V) was found to be the active species in Ru(III) catalyzed reactions. A
suitable mechanism consistent with the observations has been proposed and a rate law has been derived to
explain the kinetic orders.
Mannich Synthesis Under Ionic Liquid [Et3NH][HSO4] CatalysisIOSRJAC
Ionic liquid [Et3NH][HSO4] was found to be a particularly efficient catalyst for the synthesis of β- amino carbonyl pyrimidines through the Mannich condensation reaction of substituted pyrimidin-2(1H)-ones, cyclohexanone and 4-fluro/chlorobenzaldehyde under ultrasonic irradiation at room temperature. The present methodology offers several advantages such as excellent yields, simple procedure and mild conditions.
This is a PRESENTATION just to help students to easily understand one of the method of drug designing i.e. QSAR.. this is a combination of many slides and books..this is not my personal.
International Journal of Engineering Research and Applications (IJERA) is a team of researchers not publication services or private publications running the journals for monetary benefits, we are association of scientists and academia who focus only on supporting authors who want to publish their work. The articles published in our journal can be accessed online, all the articles will be archived for real time access.
Our journal system primarily aims to bring out the research talent and the works done by sciaentists, academia, engineers, practitioners, scholars, post graduate students of engineering and science. This journal aims to cover the scientific research in a broader sense and not publishing a niche area of research facilitating researchers from various verticals to publish their papers. It is also aimed to provide a platform for the researchers to publish in a shorter of time, enabling them to continue further All articles published are freely available to scientific researchers in the Government agencies,educators and the general public. We are taking serious efforts to promote our journal across the globe in various ways, we are sure that our journal will act as a scientific platform for all researchers to publish their works online.
Addressable Location Indicator Apparatus and MethodBrian Bissett
Addressable Location Indicator Apparatus and Method. Patent for device which provides audio and visual location indicators when triggered by a 911 call or other event.
Reactor Metabolizer virtual reactions for discovery: US UGM 2008ChemAxon
ChemAxon developed a unique virtual reaction technology that could be applied in various areas of molecule transformations. Reactor is a virtual combichem application providing synthetically feasible products using generic reactions. No reagent selection is required, and built in rules can provide chemo- regio- and stereospecificity during the library enumeration progress. A new application using the same reaction engine is introduced for the first time for the prediction of metabolic stability and xenobiotic metabolites. For latest developments see: http://www.chemaxon.com/product/reactor.html
Kinetics of Ruthenium(III) Catalyzed and Uncatalyzed Oxidation of Monoethanol...Ratnakaram Venkata Nadh
Kinetics of uncatalyzed and ruthenium(III) catalyzed oxidation of monoethanolamine by N-bromosuccinimide
(NBS) has been studied in an aqueous acetic acid medium in the presence of sodium acetate
and perchloric acid, respectively. In the uncatalyzed oxidation the kinetic orders are: the first order in NBS,
a fractional order in the substrate. The rate of the reaction increased with an increase in the sodium acetate
concentration and decreased with an increase in the perchloric acid concentration. This indicates that free
amine molecules are the reactive species. Addition of halide ions results in a decrease in the kinetic rate,
which is noteworthy. Both in absence and presence of a catalyst, a decrease in the dielectric constant of the
medium decreases the kinetic rate pointing out that these are dipole—dipole reactions. A relatively higher
oxidation state of ruthenium i.e., Ru(V) was found to be the active species in Ru(III) catalyzed reactions. A
suitable mechanism consistent with the observations has been proposed and a rate law has been derived to
explain the kinetic orders.
Mannich Synthesis Under Ionic Liquid [Et3NH][HSO4] CatalysisIOSRJAC
Ionic liquid [Et3NH][HSO4] was found to be a particularly efficient catalyst for the synthesis of β- amino carbonyl pyrimidines through the Mannich condensation reaction of substituted pyrimidin-2(1H)-ones, cyclohexanone and 4-fluro/chlorobenzaldehyde under ultrasonic irradiation at room temperature. The present methodology offers several advantages such as excellent yields, simple procedure and mild conditions.
This is a PRESENTATION just to help students to easily understand one of the method of drug designing i.e. QSAR.. this is a combination of many slides and books..this is not my personal.
International Journal of Engineering Research and Applications (IJERA) is a team of researchers not publication services or private publications running the journals for monetary benefits, we are association of scientists and academia who focus only on supporting authors who want to publish their work. The articles published in our journal can be accessed online, all the articles will be archived for real time access.
Our journal system primarily aims to bring out the research talent and the works done by sciaentists, academia, engineers, practitioners, scholars, post graduate students of engineering and science. This journal aims to cover the scientific research in a broader sense and not publishing a niche area of research facilitating researchers from various verticals to publish their papers. It is also aimed to provide a platform for the researchers to publish in a shorter of time, enabling them to continue further All articles published are freely available to scientific researchers in the Government agencies,educators and the general public. We are taking serious efforts to promote our journal across the globe in various ways, we are sure that our journal will act as a scientific platform for all researchers to publish their works online.
Addressable Location Indicator Apparatus and MethodBrian Bissett
Addressable Location Indicator Apparatus and Method. Patent for device which provides audio and visual location indicators when triggered by a 911 call or other event.
Pre coord subj hdgs to-fast 2016-04-04revJohn Riemer
Is there an emerging trend of faceted vocabularies replacing versus complementing pre-coordinated subject term usage? The payoff for adhering to a pre-coordination approach has been declining and its upkeep is increasingly a challenge. At the same time the perceived benefits of an approach like FAST are rising.
Bio-IT World 2009: Adjusting Information Flow from In-house HTS to Global Out...Brian Bissett
Adjusting Information Flow from In-house HTS to Global
Outsourcing Partners
Brian Bissett , Staff Scienti st, Molecular Properti es, Pfi zer
This talk will describe the benefi ts and pitf alls of working with a single supplier for screening
services, methods for determining if reliable data is being generated by an outsourcing partner,
and various mechanisms of acti on for manipulati ng, transferring, and integrati ng data into the
corporate environment from a foreign entity.
Renovate Your Communication Skills
Strategies for Active Listening
Eighty-percent of effective communication involves learning to be a good listener. This fun-filled, dynamic session will challenge attendees to renovate their active listening skills. To renovate means to revive, reinvigorate and/or make new. In this seminar attendees will learn how to revive their listening skills, reinvigorate the way they communicate their message and will be inspired to create new listening habits. This session is designed for those who want to be more effective in their work, build stronger relationships and make a bigger impact in their world.
Physicochemical Profiling In Drug ResearchBrian Bissett
Physicochemical and Biological Profiling in Drug Research ElogD(7.4) 20,000 Compounds Later: Refinements, Observations and Applications
Franco Lombardo, Marina Y. Shalaeva, Brian D. Bissett and Natalya Chistokhodova.
Molecular Properties Group, PGRD Groton Laboratories, Groton, CT 06340, U.S.A.
Hplc method development for proteins and polypeptides ijsit 2.4.2IJSIT Editor
In the pharmaceutical field, there is considerable interest in the use of peptides and proteins for therapeutic
purposes. High performance liquid chromatography (HPLC) and its methods of complex peptide or protein
mixtures remains a general method of choice because of the resolution it provides. Unlike small organic
molecules whose chromatographic behavior is described by a finite partitioning equilibrium between the
stationary phase and the mobile phase, proteins and peptides typically do not exhibit such an effect. Instead,
they exhibit an adsorption phenomenon in which the polypeptide is adsorbed onto the stationary phase and
elutes only when the solvent strength of the mobile phase is sufficient to compete with the hydrophobic
forces keeping it there. For this reason, elution of peptides or proteins from reversed-phase supports is by
gradients of increasing solvent strength. There are other differences that one needs to be aware of in order to
develop HPLC methods for separations of proteins and peptides as efficiently as possible.
1.Orthogonal” methods for analysis are needed in order to increase the probability that a primary assay has provided the separation (and recognition) of all peaks of interest.
2.A standardized procedure is described for the development of an “orthogonal” RP-LC separation , assuming that a primary RP-LC method for a given sample already exists.
3.An average change in resolution Rs > 3 for all adjacent peaks in the chromatogram seems likely (but not certain) to provide sufficient “orthogonality” to allow the recognition of any peaks in the “orthogonal” method that may have been overlapped and hidden in the primary method.
4.It has been demonstrated that HILIC provides different selectivity than RP-HPLC and is a useful tool for orthogonal method development.
5.Packed column SFC may provide higher separation efficiency and faster analyses with less consumption of organic solvent. SFC also offers chromatographic separation selectivity that is often similar to that of normal phase LC.
6.Results indicate that the CE method compares well with HPLC and can be used for the determination of carvedilol enantiomers in human serum. Although limits of quantitation are lower with HPLC, the CE assay offers the advantage of faster analysis times and low consumption of solvents
Introduction
Examples of Protein-Ligand interactions
Protein-Ligand Interactions Can Be Described Quantitatively
Cooperative Ligand Binding Can Be Described Quantitatively by Hill Equation
Physical and chemical methods of protein-ligand interaction study
Verification of interactions
Public protein–protein interaction databases
Ligand docking
Conclusions
References
Stability Indicating HPLC Method Development A Reviewijtsrd
High performance liquid chromatography is most powerful tools in analytical chemistry which assessing drug product stability. It is most accurate method for determining the qualitative and quantitative analysis of drug product. Forced degradation plays an important role in development of stability indicating analytical methodology. Stability indicating HPLC methods are used to separate various drug related impurities that are formed during the synthesis or manufacture of drug product. This article discusses the strategies and issues regarding the development of stability indicating HPLC system for drug substance. Forced degradation studies establish degradation pathways of drug substances and drug products. Forced degradation elucidate the possible degradation pathway of the drug substance or the active pharmaceutical ingredient in the drug product. At every stage of drug development practical recommendations are provided which will help to avoid failure. Rushikesh S Mulay | Rishikesh S Bachhav "Stability Indicating HPLC Method Development - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-6 , October 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46342.pdf Paper URL : https://www.ijtsrd.com/pharmacy/analytical-chemistry/46342/stability-indicating-hplc-method-development--a-review/rushikesh-s-mulay
Metabolomics is often described as the study of “the complete set of low molecular weight intermediates, which are context dependent, varying according to the physiology, developmental or pathological state of the cell, tissue, organ or organism”. In fact, metabolomics is a new term for an old science in which classical biochemical concepts are investigated. New and unique to the current research that is being conducted is the combination with genomics information and full system biology. In this refocus we will discuss the challenges in today's metabolomics research and how to address them
Computational modelling of drug disposition lalitajoshi9
computational modelling of drug disposition is the integral part of computer aided drug design. different kinds of tools being used in the prediction of drug disposition in human body. This topic in the CADD explains the details about the drug disposition, active transporters and tools.
Automating Data Analysis with Excel Bio-IT World 2018Brian Bissett
Automating Data Analysis with Excel was a Short Course Prepared for Bio-IT 2018 and Presented by Brian Bissett at Bio-IT World Conference on May 15, 2018 in Boston, MA.
Data Analytics of Strategic Information Technology Asset ReviewsBrian Bissett
Data Analytics of Strategic Information Technology Asset Reviews in the Office of Investment Management (OIM) Component ofat the Social Security Administration (SSA).
Chemists need numerous measurements quickly to assess the potential of a given compound within a therapeutic area. Instrumentation is expensive and of limited availability in even the most well funded organizations. The ability to share instrumentation helps mitigate equipment costs but poses special challenges to allow access and use by everyone across an organization. A solution to create open access purification equipment is presented using a Z180 microprocessor, touch screen interface, and an embedded system program written in C.
Encryption in Microsoft 365 - ExpertsLive Netherlands 2024Albert Hoitingh
In this session I delve into the encryption technology used in Microsoft 365 and Microsoft Purview. Including the concepts of Customer Key and Double Key Encryption.
Dev Dives: Train smarter, not harder – active learning and UiPath LLMs for do...UiPathCommunity
💥 Speed, accuracy, and scaling – discover the superpowers of GenAI in action with UiPath Document Understanding and Communications Mining™:
See how to accelerate model training and optimize model performance with active learning
Learn about the latest enhancements to out-of-the-box document processing – with little to no training required
Get an exclusive demo of the new family of UiPath LLMs – GenAI models specialized for processing different types of documents and messages
This is a hands-on session specifically designed for automation developers and AI enthusiasts seeking to enhance their knowledge in leveraging the latest intelligent document processing capabilities offered by UiPath.
Speakers:
👨🏫 Andras Palfi, Senior Product Manager, UiPath
👩🏫 Lenka Dulovicova, Product Program Manager, UiPath
The Art of the Pitch: WordPress Relationships and SalesLaura Byrne
Clients don’t know what they don’t know. What web solutions are right for them? How does WordPress come into the picture? How do you make sure you understand scope and timeline? What do you do if sometime changes?
All these questions and more will be explored as we talk about matching clients’ needs with what your agency offers without pulling teeth or pulling your hair out. Practical tips, and strategies for successful relationship building that leads to closing the deal.
Transcript: Selling digital books in 2024: Insights from industry leaders - T...BookNet Canada
The publishing industry has been selling digital audiobooks and ebooks for over a decade and has found its groove. What’s changed? What has stayed the same? Where do we go from here? Join a group of leading sales peers from across the industry for a conversation about the lessons learned since the popularization of digital books, best practices, digital book supply chain management, and more.
Link to video recording: https://bnctechforum.ca/sessions/selling-digital-books-in-2024-insights-from-industry-leaders/
Presented by BookNet Canada on May 28, 2024, with support from the Department of Canadian Heritage.
GraphRAG is All You need? LLM & Knowledge GraphGuy Korland
Guy Korland, CEO and Co-founder of FalkorDB, will review two articles on the integration of language models with knowledge graphs.
1. Unifying Large Language Models and Knowledge Graphs: A Roadmap.
https://arxiv.org/abs/2306.08302
2. Microsoft Research's GraphRAG paper and a review paper on various uses of knowledge graphs:
https://www.microsoft.com/en-us/research/blog/graphrag-unlocking-llm-discovery-on-narrative-private-data/
Smart TV Buyer Insights Survey 2024 by 91mobiles.pdf91mobiles
91mobiles recently conducted a Smart TV Buyer Insights Survey in which we asked over 3,000 respondents about the TV they own, aspects they look at on a new TV, and their TV buying preferences.
Generating a custom Ruby SDK for your web service or Rails API using Smithyg2nightmarescribd
Have you ever wanted a Ruby client API to communicate with your web service? Smithy is a protocol-agnostic language for defining services and SDKs. Smithy Ruby is an implementation of Smithy that generates a Ruby SDK using a Smithy model. In this talk, we will explore Smithy and Smithy Ruby to learn how to generate custom feature-rich SDKs that can communicate with any web service, such as a Rails JSON API.
Epistemic Interaction - tuning interfaces to provide information for AI supportAlan Dix
Paper presented at SYNERGY workshop at AVI 2024, Genoa, Italy. 3rd June 2024
https://alandix.com/academic/papers/synergy2024-epistemic/
As machine learning integrates deeper into human-computer interactions, the concept of epistemic interaction emerges, aiming to refine these interactions to enhance system adaptability. This approach encourages minor, intentional adjustments in user behaviour to enrich the data available for system learning. This paper introduces epistemic interaction within the context of human-system communication, illustrating how deliberate interaction design can improve system understanding and adaptation. Through concrete examples, we demonstrate the potential of epistemic interaction to significantly advance human-computer interaction by leveraging intuitive human communication strategies to inform system design and functionality, offering a novel pathway for enriching user-system engagements.
UiPath Test Automation using UiPath Test Suite series, part 4DianaGray10
Welcome to UiPath Test Automation using UiPath Test Suite series part 4. In this session, we will cover Test Manager overview along with SAP heatmap.
The UiPath Test Manager overview with SAP heatmap webinar offers a concise yet comprehensive exploration of the role of a Test Manager within SAP environments, coupled with the utilization of heatmaps for effective testing strategies.
Participants will gain insights into the responsibilities, challenges, and best practices associated with test management in SAP projects. Additionally, the webinar delves into the significance of heatmaps as a visual aid for identifying testing priorities, areas of risk, and resource allocation within SAP landscapes. Through this session, attendees can expect to enhance their understanding of test management principles while learning practical approaches to optimize testing processes in SAP environments using heatmap visualization techniques
What will you get from this session?
1. Insights into SAP testing best practices
2. Heatmap utilization for testing
3. Optimization of testing processes
4. Demo
Topics covered:
Execution from the test manager
Orchestrator execution result
Defect reporting
SAP heatmap example with demo
Speaker:
Deepak Rai, Automation Practice Lead, Boundaryless Group and UiPath MVP
UiPath Test Automation using UiPath Test Suite series, part 3DianaGray10
Welcome to UiPath Test Automation using UiPath Test Suite series part 3. In this session, we will cover desktop automation along with UI automation.
Topics covered:
UI automation Introduction,
UI automation Sample
Desktop automation flow
Pradeep Chinnala, Senior Consultant Automation Developer @WonderBotz and UiPath MVP
Deepak Rai, Automation Practice Lead, Boundaryless Group and UiPath MVP
GDG Cloud Southlake #33: Boule & Rebala: Effective AppSec in SDLC using Deplo...James Anderson
Effective Application Security in Software Delivery lifecycle using Deployment Firewall and DBOM
The modern software delivery process (or the CI/CD process) includes many tools, distributed teams, open-source code, and cloud platforms. Constant focus on speed to release software to market, along with the traditional slow and manual security checks has caused gaps in continuous security as an important piece in the software supply chain. Today organizations feel more susceptible to external and internal cyber threats due to the vast attack surface in their applications supply chain and the lack of end-to-end governance and risk management.
The software team must secure its software delivery process to avoid vulnerability and security breaches. This needs to be achieved with existing tool chains and without extensive rework of the delivery processes. This talk will present strategies and techniques for providing visibility into the true risk of the existing vulnerabilities, preventing the introduction of security issues in the software, resolving vulnerabilities in production environments quickly, and capturing the deployment bill of materials (DBOM).
Speakers:
Bob Boule
Robert Boule is a technology enthusiast with PASSION for technology and making things work along with a knack for helping others understand how things work. He comes with around 20 years of solution engineering experience in application security, software continuous delivery, and SaaS platforms. He is known for his dynamic presentations in CI/CD and application security integrated in software delivery lifecycle.
Gopinath Rebala
Gopinath Rebala is the CTO of OpsMx, where he has overall responsibility for the machine learning and data processing architectures for Secure Software Delivery. Gopi also has a strong connection with our customers, leading design and architecture for strategic implementations. Gopi is a frequent speaker and well-known leader in continuous delivery and integrating security into software delivery.
State of ICS and IoT Cyber Threat Landscape Report 2024 previewPrayukth K V
The IoT and OT threat landscape report has been prepared by the Threat Research Team at Sectrio using data from Sectrio, cyber threat intelligence farming facilities spread across over 85 cities around the world. In addition, Sectrio also runs AI-based advanced threat and payload engagement facilities that serve as sinks to attract and engage sophisticated threat actors, and newer malware including new variants and latent threats that are at an earlier stage of development.
The latest edition of the OT/ICS and IoT security Threat Landscape Report 2024 also covers:
State of global ICS asset and network exposure
Sectoral targets and attacks as well as the cost of ransom
Global APT activity, AI usage, actor and tactic profiles, and implications
Rise in volumes of AI-powered cyberattacks
Major cyber events in 2024
Malware and malicious payload trends
Cyberattack types and targets
Vulnerability exploit attempts on CVEs
Attacks on counties – USA
Expansion of bot farms – how, where, and why
In-depth analysis of the cyber threat landscape across North America, South America, Europe, APAC, and the Middle East
Why are attacks on smart factories rising?
Cyber risk predictions
Axis of attacks – Europe
Systemic attacks in the Middle East
Download the full report from here:
https://sectrio.com/resources/ot-threat-landscape-reports/sectrio-releases-ot-ics-and-iot-security-threat-landscape-report-2024/
Essentials of Automations: Optimizing FME Workflows with ParametersSafe Software
Are you looking to streamline your workflows and boost your projects’ efficiency? Do you find yourself searching for ways to add flexibility and control over your FME workflows? If so, you’re in the right place.
Join us for an insightful dive into the world of FME parameters, a critical element in optimizing workflow efficiency. This webinar marks the beginning of our three-part “Essentials of Automation” series. This first webinar is designed to equip you with the knowledge and skills to utilize parameters effectively: enhancing the flexibility, maintainability, and user control of your FME projects.
Here’s what you’ll gain:
- Essentials of FME Parameters: Understand the pivotal role of parameters, including Reader/Writer, Transformer, User, and FME Flow categories. Discover how they are the key to unlocking automation and optimization within your workflows.
- Practical Applications in FME Form: Delve into key user parameter types including choice, connections, and file URLs. Allow users to control how a workflow runs, making your workflows more reusable. Learn to import values and deliver the best user experience for your workflows while enhancing accuracy.
- Optimization Strategies in FME Flow: Explore the creation and strategic deployment of parameters in FME Flow, including the use of deployment and geometry parameters, to maximize workflow efficiency.
- Pro Tips for Success: Gain insights on parameterizing connections and leveraging new features like Conditional Visibility for clarity and simplicity.
We’ll wrap up with a glimpse into future webinars, followed by a Q&A session to address your specific questions surrounding this topic.
Don’t miss this opportunity to elevate your FME expertise and drive your projects to new heights of efficiency.
DevOps and Testing slides at DASA ConnectKari Kakkonen
My and Rik Marselis slides at 30.5.2024 DASA Connect conference. We discuss about what is testing, then what is agile testing and finally what is Testing in DevOps. Finally we had lovely workshop with the participants trying to find out different ways to think about quality and testing in different parts of the DevOps infinity loop.
2. RP-HPLC Lipophilicity Determination Journal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2923
concern, if the data were to be used for software training
purposes or for the creation of a large database, is the
reproducibility from column to column, that is, the
reproducibility of the packing chemistry and manufac-
turing. It might be argued that a well-kept column
would last for a considerably long period of time, but it
is essential to know that pooling data from different
columns will not be difficult, although “scaling stan-
dards” might be used across columns. However, tests
of reproducibility of the method from column to column
should be performed, independently of the above argu-
ments.
The speed of the determination and the ability to
handle diverse structures and lipophilicity values are,
of course, of paramount importance in an industrial
research setting. These aspects translate into the ca- Figure 1. Correlation between logPoct and k′ for 27 solutes,
w
pability of screening, with fairly modest resources, a in the absence of octanol.
fairly large number of compounds, with a good degree
of accuracy across a wide range of lipophilicity values initially and after 4 months of intensive use, and no
and hydrogen-bonding properties. significant difference was found. Therefore, we con-
Considering the points discussed above, we set out cluded that the difference in performance was brought
to develop a method that would be accurate, rapid, and about by the addition of octanol to both components of
possess a good dynamic range, together with being the mobile phase and not by potential differences in the
applicable to a variety of drug-like molecules, albeit column packing among individual columns.
neutral ones in the present work. We present and Figures 1 and 2 clearly bring out the significant
discuss our results in the following sections. difference between the addition of 1-octanol to the
mobile phase (both components), with respect to the
Results and Discussion data generated in its absence. In both cases the slope
is close to unity, but the error is more than doubled in
Minick at al.7,12 had used a MC-8 column, coupled the absence of 1-octanol as expressed by eq 1 (no added
with the addition of 1-octanol to both components of the octanol) and eq 2 (added octanol). In both cases a range
eluent, together with the addition of small amounts of of 6 logPoct units is encompassed by these experiments.
n-decylamine in the aqueous phase. We reasoned that
an electrostatically coated silica phase13 (such as the LC- log Poct )
ABZ column) might not require a modifier such as 1.0890((0.0969) log k′ - 0.5435((0.2768) (1)
w
n-decylamine. At the same time octanol might be
beneficial to reproduce the intermolecular interactions N ) 27, R2 ) 0.835, R ) 0.914,
experienced by a solute in a classical “shake-vial”
s ) 0.556, F ) 126, q2 ) 0.808
octanol/buffer partition determination, and it might
reduce (however slightly) the retention times. Thus we log Poct )
“combined” the column used by Pagliara et al.6 with the 1.1014((0.0389) log k′ - 0.0045((0.0941) (2)
w
conditions used by Minick et al.,7 with the exception of
the use of n-decylamine, and explored its application to N ) 27, R2 ) 0.970, R ) 0.985,
a set of diverse drug-like compounds. To maximize the
s ) 0.238, F ) 803, q2 ) 0.965
speed of analysis, while still retaining a good accuracy,
an appropriate flow rate was chosen for each range of The question of the diagnostic importance of the slope
lipophilicity (see Experimental Section), and this choice has been stressed by Minick et al.12 Pointing to the work
was combined with the use of a fairly short column to of Melander et al.,14 these authors state that “...equa-
further enhance the throughput of the method. tions correlating log k′ and logPoct data represent
w
The data we obtained for an initial set of 27 com- linear free energy relationships in which the slope is
pounds, in the absence or presence of octanol, pointed an estimate of how closely the free energies of the
to a clear difference in performance, as shown by processes compare.” A slope close to unity implies that
Figures 1 and 2, and by their respective equations. The the two processes are homoenergetic, i.e., the free energy
compounds used are the first 27 compounds reported changes are the same. In our case a slope very close to
in Table 1. The data used in Figure 1 were generated unity is obtained, with or without 1-octanol. Further-
using only methanol and MOPS buffer as the mobile more a larger slope would result in the magnification
phase, as opposed to Figure 2, where octanol was added of any error in the determination of log k′ if thew
to methanol, and octanol-saturated water was used to estimation of logPoct was the final goal. The log k′ data
w
prepare the buffer. In both cases the flow rate was 1 could be used as a self-consistent scale of lipophilicity
mL/min. Different columns were used for these runs, and, in this case, the second consideration would not
but the intercolumn variability was checked (via the be very important. An example might be represented
protocol used in Figure 2, data not shown), and an by the work of Valko et al.,15 which describes a chro-
´
excellent correlation was obtained for the three different matographic hydrophobicity index (CHI), obtained via
columns used. In one case, the same column was tested a gradient run. In this case a correlation with a
3. 2924 Journal of Medicinal Chemistry, 2000, Vol. 43, No. 15 Lombardo et al.
Figure 3. Correlation between logPoct and k′ for 36 solutes.
w
Figure 2. Correlation between logPoct and k′ for 27 solutes, aiming at extending the physicochemical diversity of the
w
in the presence of octanol. set. We added nine more compounds, as reported in
Table 1, and sought, at the same time, an analysis of
“classical” shake-flask logPoct was not necessarily sought, the data via the well-known solvation parameters of
and a self-consistent CHI scale was established. How- Abraham.16,17 The solvation analysis was performed to
ever, logPoct (or logDoct) data are so widely used in many answer the question of closeness between the classical
correlations by the medicinal chemistry community that shake flask logPoct values,and our RP-HPLC derived
a “classical” logPoct value is likely to be desired. To the values, beyond what could be surmised by a slope close
best of our knowledge no other method capable of to unity.
encompassing all the accuracy and ruggedness require- Figure 3 shows, graphically, the correlation between
ments we set as goals for this work has been reported the shake-flask and the corresponding RP-HPLC data.
in the literature to date. Also, the slope in eq 3 is very similar to the slope in eq
Armed with these very good results, we sought to 2, further demonstrating the accuracy of the method and
expand the correlation by adding more drug compounds, yielding an indirect assessment of its robustness in
Table 1. Retention Time and logPoct Data for the 36 Solutes Used
compound CAS no. log k′ a
w Elog Poctb log Poctc residuals refsd
3,5-dichlorophenol 591-35-5 3.40 3.88 3.68 -0.20 11
3-bromoquinoline 5332-24-1 2.54 2.93 3.03 0.10 11
3-chlorophenol 108-43-0 2.49 2.88 2.50 -0.38 20
acetaminophen 103-90-2 -0.02 0.11 0.51 0.40 21
acetophenone 98-86-2 1.31 1.58 1.58 0.00 20
allopurinol 315-30-0 -0.89 -0.85 -0.55 0.30 22
bromazepam 1812-30-2 1.13 1.38 1.65 0.27 23
carbamazepine 298-46-4 1.70 2.01 2.19 0.18 24
chloramphenicol 56-75-7 1.18 1.43 1.14 -0.29 25
clotrimazole 23593-75-1 4.13 4.69 5.20 0.51 e
dexamethasone 50-02-2 2.03 2.37 1.83 -0.54 26
diazepam 439-14-5 2.63 3.03 2.79 -0.24 27
estradiol 50-28-2 3.34 3.82 4.01 0.19 25
fluconazole 86386-73-4 0.37 0.54 0.50 -0.04 19
griseofulvin 126-07-8 2.21 2.57 2.18 -0.39 25
hydrocortisone 50-23-7 1.43 1.71 1.55 -0.16 26
hydrocortisone-21-acetate 50-03-3 1.93 2.26 2.19 -0.07 26
lorazepam 846-49-1 2.36 2.74 2.51 -0.23 28
lormetazepam 848-75-9 2.40 2.78 2.72 -0.06 29
naphthalene 91-20-3 3.06 3.51 3.37 -0.14 11
nifedipine 21829-25-4 2.46 2.85 3.17 0.32 this work
nifuroxime 6236-05-1 1.11 1.36 1.28 -0.08 this work
prednisolone 50-24-8 1.54 1.83 1.60 -0.23 this work
prednisone 53-03-2 1.21 1.47 1.46 -0.01 25
quinoline 91-22-5 1.56 1.85 2.03 0.18 30
testosterone 58-22-0 2.74 3.15 3.29 0.14 26
tolnaftate 2398-96-1 4.55 5.15 5.40 0.25 e
antipyrine 60-80-0 0.09 0.23 0.38 0.15 31
bifonazole 60628-96-8 4.37 4.95 4.77 -0.18 25
caffeine 58-08-2 -0.31 -0.21 -0.07 0.14 25
diethylstilbestrol 56-53-1 4.16 4.72 5.07 0.35 25
methylthioinosine 342-69-8 0.19 0.34 0.09 -0.25 this work
metronidazole 443-48-1 -0.32 -0.22 -0.02 0.20 32
nitrofurazone 59-87-0 0.10 0.24 0.23 -0.01 33
pentoxifylline 6493-05-6 0.16 0.31 0.29 -0.02 34
thiamphenicol 15318-45-3 -0.24 -0.13 -0.27 -0.14 35
a Average of at least three determinations on different LC-ABZ columns (average s.d. ) 0.119). b Data from eq 3. c Shake-flask data.
d References for shake-flask data. e Computed values using ClogP 3.55 v.210.
4. RP-HPLC Lipophilicity Determination Journal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2925
Figure 4. Plot of residuals vs logPoct.
Figure 5. Control plot for nifuroxime.
predicting unknown compounds. The cross-validated and we will refer to them as such for the rest of the
coefficient of determination (leave-one-out), or q2 value, discussion.
shows the excellent predictive power of this method. The We then turned our attention to an analysis of the
correlation was obtained by averaging the values de- balance of forces underlying these phenomena, using a
termined, for each compound, using a minimum of three linear free energy relationship, based on solvation
different columns, with an average standard deviation parameters, as described by Abraham.16,17 In these
of 0.1187. equations R2 is the excess molar refraction, πH is the
2
dipolarity/polarizability, ∑RH and ∑β0 are the (sum-
2 2
log Poct ) mation) hydrogen bond acidity and basicity, respec-
1.1021((0.0291) log k′ + 0.1344((0.0653) (3)
w tively, and VX is the McGowan’s volume. In particular,
the superscript “0”, used for the hydrogen bond basicity
N ) 36, R2 ) 0.977, R ) 0.988, parameter, refers to a particular scale of values, useful
s ) 0.251, F ) 1434, q2 ) 0.974 for certain types of solutes, when the organic portion of
the binary system is a partially water miscible solvent,
Furthermore it is worth noting that a plot of residuals as in the case of water-saturated octanol. The other
vs the logPoct values, as in Figure 4, shows that the error subscripts and superscripts have the usual meaning,
distribution is very consistent across the entire range, i.e., they refer to hydrogen-bonding scales and to the
and no curvature (larger error) is observed at extreme solute.16a The calculated parameters are reported in
values. This is important because it shows that similarly Table 2, and the coefficients for the respective equations
accurate determinations can be obtained across 6 logPoct (eq 4 and 5), whether log k′ or ElogPoct values are
w
units. used, are very close to the coefficients of the equation
As a further measure for a day-to-day system suit- based on shake-flask logPoct values (eq 6), as reported
ability check, we used control charts, constructed for 10 for 613 solutes,17 as well as to the equation based on
compounds suitably chosen across the entire range, as shake-flask values for the 35 solutes examined (eq 7).
shown in Figure 5 for nifuroxime (see Statistical Analy- We note that (i) the correlation matrix (Table 3) is
sis section). An unexpected variation in these plots satisfactory and (ii) the comparison between eqs 4 and
would immediately “flag” questionable results. 5 shows that the correlation between log k′ and the
w
We termed the values obtained via eq 3 as ElogPoct, shake-flask values relies on the same balance of forces
5. 2926 Journal of Medicinal Chemistry, 2000, Vol. 43, No. 15 Lombardo et al.
Table 2. Solvation Parameters for 35 Solutes E log Poct ) 0.204((0.015) + 0.452((0.117)R2 -
compound R2 πH
2 ∑RH
2 ∑β0
2 VX 1.053((0.086)πH - 0.041((0.120)
2 ∑RH - 3.410((
2
3,5-dichlorophenol
3-bromoquinoline
1.02
1.64
1.00
1.23
0.91
0.00
0.00
0.42
1.0199
1.2193 0.111) ∑β0 + 3.842((0.104)VX
2 (5)
3-chlorophenol 0.91 1.06 0.69 0.15 0.8975
acetominophen 1.06 1.63 1.04 0.86 1.1724 N ) 35, R2 ) 0.980, R ) 0.990, s ) 0.244, F )
acetophenone 0.82 1.01 0.00 0.48 1.0139 288, q2 ) 0.968
allopurinol 1.41 1.55 0.70 0.92 0.8818
∑πH -
bromazepam 2.31 1.38 0.33 1.62 1.9445
carbamazepine 2.15 2.07 0.52 1.13 1.8106 log Poct ) 0.088 + 0.562R2 - 1.054 2
chloramphenicol
clotrimazole
1.85
2.55
0.72
2.60
0.34
0.00
2.09
1.08
2.0728
2.6230
0.034∑RH - 3.460∑β0 + 3.814VX
2 2 (6)
dexamethasone 2.04 3.51 0.71 1.92 2.9132
diazepam 2.08 1.57 0.00 1.25 2.0739 N ) 613, R2 ) 0.995, R ) 0.997, s ) 0.116, F )
estradiol 1.80 1.77 0.86 1.10 2.1988 23162
fluconazole 2.34 2.80 0.47 1.65 2.0064
griseofulvin 1.75 2.69 0.00 1.50 2.3947 log Poct ) 0.273((0.103) + 0.525((0.076)R2 - 1.034
hydrocortisone 2.03 3.49 0.71 1.90 2.7976
hydrocortisone-21-acetate 1.89 2.88 0.46 2.16 3.0951 ((0.056)πH - 0.049((0.078)
2 ∑RH - 3.510((
2
∑β0 + 3.787((0.091)VX
lorazepam 2.51 1.28 0.45 1.63 2.1141
lormetazepam 2.44 1.65 0.12 1.61 2.2550 0.072) 2 (7)
naphthalene 1.34 0.92 0.00 0.20 1.0854
nifedipine 1.50 2.45 0.23 1.45 2.4945 N ) 35, R2 ) 0.992, R ) 0.996, s ) 0.16, F ) 705
nifuroxime 1.13 0.98 0.69 0.60 0.9669
prednisolone 2.21 3.10 0.71 1.92 2.7546
prednisone 2.14 3.58 0.36 1.89 2.7116
As a further improvement we have also automated
quinoline 1.27 0.97 0.00 0.54 1.0443 the calculation procedure, through in-house software,
testosterone 1.54 2.59 0.32 1.19 2.3827 to obtain the final ElogPoct value, without any manual
tolnaftate 2.97 2.20 0.00 0.93 2.3949 intervention, directly from the chromatographic data
antipyrine 1.32 1.50 0.00 1.48 1.5502 file. This modification allows for an enhanced through-
bifonazole 2.41 2.25 0.00 1.12 2.5006
caffeine 1.50 1.60 0.00 1.33 1.3632 put, starting with an already rapid procedure. ElogPoct
diethylstilbestrol 1.60 1.75 1.26 0.77 2.2440 data for any compound are obtained, on average, in 20
metronidazole 1.05 1.60 0.18 1.03 1.1919 min or less, on a single instrument.
nitrofurazone 1.65 1.79 0.40 1.08 1.2644 The current method is, at the moment, limited to
pentoxifylline 1.64 2.28 0.00 1.84 2.0834
thiamphenicol 2.26 3.30 0.90 2.03 2.3204 neutral (and weakly acidic or basic) compounds, but its
development covers the practical limitation involved in
Table 3. Correlation Matrix for the 35 Solutes in Table 2a the determination of compounds which are devoid of any
significant ionization, and thus are not amenable to a
πH
2 ∑RH
2 ∑β0
2 VX logPoct determination via well-known potentiometric
R2 0.234 0.017 0.325 0.519 techniques.18
πH
2
0.024 0.434 0.630
∑RH2
0.001 0.001 Conclusion
∑β02
0.576
We have demonstrated that, by a judicious choice of
a R2 values. mobile phase and RP-HPLC column, a very accurate
ElogPoct determination method could be developed which
encoded by the two parameters, beyond a slope of unity. responds to the criteria of rapid throughput, ruggedness,
Furthermore any cross-correlation of the parameters, and minimal manual intervention set forth in the
for the data reported in this paper, does not affect the Introduction, for drug-like compounds. Since logPoct has
coefficients of eq 7 as compared to eq 6. Also, the ratios been shown to be an important parameter for the ADME
of coefficients, normalized to the VX coefficient, are profiling of newly synthesized compounds,3 such as
essentially identical for all four equations (data not estimation of solubility, intestinal permeability, and
shown). We conclude that the ElogPoct values, obtained clearance, we believe this method will find useful
using the method presented here, and expressed by eq applications in pharmaceutical discovery and develop-
3, are identical to shake-flask values, but they can be ment settings. Work is in progress to find a similarly
generated at a much higher throughput, and combine rugged and efficient method for the determination of
ease of operation with a wide dynamic range. Due to logDoct values, at pH 7.4. These findings will be reported
lack of partition data in other solvent pairs, we were in due course.
not able to obtain accurate parameters for methylthio- Experimental Section
inosine, and this solute was excluded from the correla-
Materials and Methods. All the solutes were purchased
tion.
directly from commercial sources (Aldrich, Sigma, and Fluka)
and used as received, in all cases. Fluconazole was obtained
log k′ ) 0.066((0.144) + 0.409((0.106)R2 - 0.955
w
internally. Deionized water, HPLC grade methanol (J. P.
Baker), and 1-octanol (Fisher Scientific) were used throughout.
((0.078)πH - 0.038((0.109)
2 ∑RH - 3.092((
2 The mobile phase consisted, in all cases, of 20 mM MOPS
0.101) ∑ β0
2 + 3.484((0.127)VX (4) buffer at pH 7.4 and methanol in varying proportions from 70
to 15% v/v. A 0.25% (v/v) amount of octanol was added to
methanol, and octanol-saturated water was used to prepare
N ) 35, R2 ) 0.980, R ) 0.990, s ) 0.221, F ) the buffer, with the exception of the correlation obtained
288, q2 ) 0.970 without octanol in either component of the mobile phase (vide
6. RP-HPLC Lipophilicity Determination Journal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2927
infra). The capacity factors data (k′ ) (tR - t0)/ t0), obtained at References
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